Project Summary Dendritic cells (DCs) are potent professional antigen presenting cells of the immune system and serve as a bridge between innate and adaptive immune responses. When DCs are activated by a stimulus through toll- like receptors (TLRs), DCs undergo a process of maturation, defined by cytokine & chemokine secretion, co- stimulatory molecule expression, antigen processing and presentation, and the ability to activate T cells. DC maturation is coupled with an increase in energy demand, which is fulfilled by a TLR-driven burst in glycolytic metabolism. Up-regulation of glycolysis in activated DCs provides these cells with molecular building blocks and cellular energy required for DC effector function. Inhibition of glycolysis impairs both the survival and effector function of activated DCs. According to the prevailing model in the field of DC ?immunometabolism?, TLR-driven glycolysis in DCs is sustained primarily by increases in glucose uptake. While non-immune cells, specifically hepatocytes and muscle cells, can store glucose in the form of glycogen as an intracellular energy reserve, the role of glycogen metabolism in supporting DC immune responses has not been described. Our preliminary data show that DCs express enzymes essential for glycogen metabolism and that inhibition of glycogen metabolism significantly impairs key activation parameters of these cells. This indicates that glycogen metabolism in DCs may play an important role in supporting the effector function of DCs. This proposal aims to answer how glycogen metabolism regulates and supports the course of immune activation in DCs. We propose using a combination of pharmacological and genetic approaches in both human and mouse DC systems to test the hypothesis that glycogen metabolism is an essential component of DC energy homeostasis that is required for supporting effective immune functions of these cells. !